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Differences between binding of one-chain and two-chain tissue plasminogen
activators to non-cross-linked and cross-linked fibrin clots
SS Husain, AA Hasan and AZ Budzynski
Department of Biochemistry, Temple University School of Medicine,
Philadelphia, PA 19140.
Interaction of tissue plasminogen activator (t-PA) with fibrin plays a key
role in regulation of plasminogen activation and clot dissolution. Previous
investigations of t-PA-fibrin interaction, using incorporation of t-PA into
polymerizing fibrin clots, have suggested that no significant differences
exist in the binding of one-chain or two-chain t-PA to non-cross-linked or
cross-linked fibrin. In the present study, binding of 125I-labeled and
affinity-purified one-chain and two-chain forms of t-PA to preformed
non-cross-linked or cross-linked, sonicated suspension of fibrin was
investigated. Interaction of one-chain t-PA with cross-linked fibrin
involved a single type of binding site with dissociation constant (kd) of
0.58 mumol/L and a stoichiometry (n) of 1.5. Interaction of one-chain t-PA
with non-cross-linked fibrin, however, involved two classes of binding
sites with dissociation constants of 0.32 and 1.5 mumol/L and corresponding
number of binding sites equal to 0.57 and 2.0, respectively. In contrast to
the binding of one-chain t-PA to cross-linked fibrin by a limited number of
sites, two-chain t-PA appeared to involve a considerably greater number of
sites (minimum six) whose dissociation constant was 3.2 mumol/L.
Interaction of two-chain t-PA with non-cross-linked fibrin also showed the
presence of many binding sites (minimum seven) with approximate
dissociation constant of 6.4 mumol/L, as well as a few (n = 0.012) high-
affinity sites with a kd of 0.011 mumol/L epsilon-Aminocaproic acid did not
completely reverse the binding of either one-chain t-PA or two- chain t-PA
to fibrin. The present findings suggest that the fibrin- binding properties
of t-PA undergo considerable changes on proteolytic conversion from
one-chain to two-chain t-PA, catalyzed under physiologic conditions by
plasmin. The cleavage of one-chain t-PA to two-chain t-PA allows to bind to
a large number of low-affinity binding sites on fibrin. Cross-linking of
fibrin by factor XIIIa results in masking of high-affinity binding sites
that are present in non-cross- linked fibrin. We propose that both plasmin
and factor XIIIa play an important regulatory role in dissolution of blood
clots by modulating t- PA-fibrin interaction.
Volume 74,
Issue 3,
pp. 999-1006,
08/15/1989
Copyright © 1989 by The American Society of Hematology
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